title: The serine hydrolase ABHD6 Is a critical regulator of the metabolic syndrome.
abstract: The serine hydrolase α/β hydrolase domain 6 (ABHD6) has recently been implicated as a key lipase for the endocannabinoid 2-arachidonylglycerol (2-AG) in the brain. However, the biochemical and physiological function for ABHD6 outside of the central nervous system has not been established. To address this, we utilized targeted antisense oligonucleotides (ASOs) to selectively knock down ABHD6 in peripheral tissues in order to identify in vivo substrates and understand ABHD6's role in energy metabolism. Here, we show that selective knockdown of ABHD6 in metabolic tissues protects mice from high-fat-diet-induced obesity, hepatic steatosis, and systemic insulin resistance. Using combined in vivo lipidomic identification and in vitro enzymology approaches, we show that ABHD6 can hydrolyze several lipid substrates, positioning ABHD6 at the interface of glycerophospholipid metabolism and lipid signal transduction. Collectively, these data suggest that ABHD6 inhibitors may serve as therapeutics for obesity, nonalcoholic fatty liver disease, and type II diabetes.
authors.affiliation: Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Gwynneth
authors.initials: G
authors.lastname: Thomas
authors.affiliation: Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Betters
authors.affiliation: Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Caleb C
authors.initials: CC
authors.lastname: Lord
authors.affiliation: Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.|New Affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland OH 44195, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Brown
authors.affiliation: Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.|New Affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland OH 44195, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Marshall
authors.affiliation: Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.|New Affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland OH 44195, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ferguson
authors.affiliation: Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Sawyer
authors.affiliation: Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Davis
authors.affiliation: Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Melchior
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Blume
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Allyn C
authors.initials: AC
authors.lastname: Howlett
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Pavlina T
authors.initials: PT
authors.lastname: Ivanova
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Milne
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Myers
authors.affiliation: Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria.
authors.forename: Irina
authors.initials: I
authors.lastname: Mrak
authors.affiliation: Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria.
authors.forename: Vera
authors.initials: V
authors.lastname: Leber
authors.affiliation: Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Heier
authors.affiliation: Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Taschler
authors.affiliation: Deparment of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Jacqueline L
authors.initials: JL
authors.lastname: Blankman
authors.affiliation: Deparment of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.affiliation: Cardiovascular Group, Antisense Drug Discovery, Isis Pharmaceuticals, Inc., Carlsbad, CA 92010 USA.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Lee
authors.affiliation: Cardiovascular Group, Antisense Drug Discovery, Isis Pharmaceuticals, Inc., Carlsbad, CA 92010 USA.
authors.forename: Rosanne M
authors.initials: RM
authors.lastname: Crooke
authors.affiliation: Cardiovascular Group, Antisense Drug Discovery, Isis Pharmaceuticals, Inc., Carlsbad, CA 92010 USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Graham
authors.affiliation: Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Zimmermann
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: H Alex
authors.initials: HA
authors.lastname: Brown
authors.affiliation: Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.|New Affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland OH 44195, USA.
authors.forename: J Mark
authors.initials: JM
authors.lastname: Brown
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D059305:Diet, High-Fat; D063388:Endocannabinoids / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000517:prevention & control; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction
chemical_list: C543264:Cnr1 protein, rat; D063388:Endocannabinoids; D005227:Fatty Acids; D016376:Oligonucleotides, Antisense; D043884:Receptor, Cannabinoid, CB1; C527261:ABHD6 protein, mouse; D008994:Monoacylglycerol Lipases